대한통증학회지 2004; 17: 234-238 Korean J Pain Vol. 17, No. 2, 2004
Effect of Tramadol/Acetaminophen Combination Tablets in the Treatment of Chronic Pain Seung Hoon Baek, M.D., Chul Hong Kim, M.D., Kyung Hoon Kim, M.D., Sang Wook Shin, M.D., Hae Kyu Kim, M.D., and Seong Wan Baik, M.D. Department of Anesthesiology and Pain Medicine, College of Medicine, Pusan National University, Busan, Korea = Abstract =
Background: The aim of this study was to evaluate the efficacy of a tramadol/acetaminophen combination tablet in chronic pain management. Methods: Two hundred fifty five adult patients, suffering from chronic pain, were administered tramadol/acetaminophen combination tablets for at least 4 weeks. The analgesic effect from the start to the finish of the study was evaluated by a numeric rating scale (NRS, from 0 to 10). The pain relief score was also recorded (initial NRS-final NRS), which was allocated as follows: no change (0 or aggravation), moderate (1-2), notable (3-4) or significant pain relief (5 or more). The usefulness of the tramadol/acetaminophen combination tablet was rated according to the NRS, the pain relief score, the appearance of side effect and the patient's response, and categorized as not useful, useful or very useful. Results: The mean NRS score decreased from 6.1 to 3.5. The pain relief scores were no relief, moderate relief notable relief, significant relief and not assessed in 17, 108, 95, 23 and 3, respectively. Side effects developed in only 5.7% of the 246 patients. Conclusions: It was concluded that tramadol/acetaminophen combination tablet therapy had an additive effect in the treatment of chronic pain management when combined with other analgesics. (Korean J Pain 2004; 17: 234-238) ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Key Words: Pain, Tramadol/Acetaminophen combination tablet.
receptors in the central nervous system and also inhibits the reuptake of norepinephrine and serotonin. Tramadol is an
INTRODUCTION
effective analgesic agent in the treatment of moderate to modModern pharmacological pain management is based on non-
erately severe acute or chronic pain.1) Acetaminophen, known
opioid and opioid analgesics. Tramadole/acetaminophen combi-
as paracetamol, is a nonsteroidal anti-inflammatory drug with
nation tablet is a combination analgesic product containing a
potent antipyretic and analgesic actions but with very weak
centrally acting synthetic analgesic (tramadol hydrochloride) and
anti-inflammatory activity. The exact mechanism of action is
an agent that inhibits prostaglandin synthesis in the central ner-
unknown. Acetaminophen is primarily centrally acting, has no
vous system and blocks pain impulses in the peripheral ner-
effects on platelet aggregation, and is a reversible inhibitor of
vous system (acetaminophen). Tramadol is referred to as an a-
cyclooxygenase, an enzyme involved in prostaglandin (PG)
typical opioid because it had opioid and nonopioid mechanisms
synthesis. An analgesic effect may be produced by a direct
of action. Tramadol binds weakly as an agonist to the μ-opioid
action on the pain threshold. This effect is believed to be due to the inhibition of PG synthesis or the inhibition of the synthesis or actions of chemical mediators or other substances that
Corresponding to：Seong Wan Baik, Department of Anesthesia and Pain Medicine, College of Medicine, Pusan National University, 1-10, Ami-dong, Seo-gu, Busan 602-739, Korea. Tel: +82-51-240-7391, Fax: +82-51-242-7466 E-mail:
[email protected] This study was supported by Janssen Korea Limited.
sensitize the pain receptors to mechanical or chemical stimulation.2-4) A previously used combination drug, oxycodone with aceta5)
minophen, is effective in management of acute or chronic pain.
Adding acetaminophen to weak opioids can increase the anal234
SH Baek, et al：Tramadol/Acetaminophen Combination Tablets for Chronic Pain Treatment
gesic potency of the opioid component. Tramadol/acetaminophen combination tablet is composed of 37.5 mg of tramadol hydrochloride and 325 mg of acetaminophen per tablet.
235
tained in the patients with effective pain relief. The effect was evaluated by NRS from its first administration until the finish of the study in an outpatient clinic or
The aim of this study was to evaluate efficacy of tramadole/
hospital room. In order to determine the effect of pain relief,
acetaminophen combination tablet in treatment of chronic pain
the NRS score change was calculated (the initial NRS score-
management.
final NRS score) and grouped into 4 categories. Pain relief was evaluated as follows: aggravation or no change was no re-
MATERIALS AND METHODS
lief, a score change of 1 or 2 was moderate, a score change 3 or 4 was notable, and a score change of more than 5 was sig-
This study was a multiclinic and outpatient/inpatient study.
nificant pain relief. Also, a physician evaluated the effect as
Two hundred and fifty-five patients were administered tramadol/
not useful, useful, or very useful. Side effects were recorded at
Ⓡ
Janssen Korea) for
each visit. In cases of those who getting severe, the dosage of
the treatment of chronic pain. Three patients could not be as-
tramadol/acetaminophen combination tablet was reduced. The
sessed on a numeric rating scale (NRS), because they stopped
result of the effect of drug was examined using a paired t-
visiting our hospital after 4 weeks. Additional inclusion criteria
test. A P value (0.01 was considered ststistically significant.
acetaminophen combination tablet (Ultracet
were an NRS of more than 4 (9 patients were excluded) at the start of study, and an age between 21 and 96 years old. All
RESULTS
patients were required to be able to read and comprehend written instructions and to complete the pain assessment forms. In
The mean age was 46.1 years; 46 patients suffered from
most of patients the study was processed more than 4 weeks,
cancer pain, 64 patients from musculoskeletal pain, 29 patients
without any change in the dosage of previously administered
from neuropathy, 87 patients from osteoarthritis (OA) or rheu-
analgesics. Thirty three patients were administered tramadol/
matic arthritis (RA), and 20 patients from other pain. There
acetaminophen combination tablet as the first analgesics, and
were 161 female patients, and 94 male patients. The mean ini-
213 patients added tramadol/acetaminophen combination tablet
tial tramadol/acetaminophen combination tablet dosage was 2.5
from other analgesics administered previously. The initial dose
tablet, and the final dosage was 2.9 tablet. Among the pa-
was determined by the initial NRS, the dosage of other drugs,
tients, 33 took tramadol/acetaminophen combination tablet as
the origin of pain, and the patients' age. After 1week of ad-
the initial anagesic, whereas the remaining patients were
ministeration, the dosage was increased in the patients with ineffective pain relief by one tablet, and the dosage was main-
Table 1. Patient Number, Age, Sex, NRS, Dose of Tramadol/ Acetaminophen Combination Tablet and Development of Side Effects ꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧꠧ Patients Age (yr) Sex (M/F) NRS ratio Dose ratio SE ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ A 46 42.2 22/24 5.2/2.3 3.2/3.7 8 B 64 49.5 38/26 6.4/3.8 3.1/3.2 3 C 29 48.0 19/10 7.2/4.6 2.9/3.1 0 D 87 43.5 17/70 6.1/3.8 2.1/2.2 2 M 20 51.9 9/11 6.2/1.2 2.5/2.5 1 Total 246 44.6 105/141 6.1/3.5 2.5/2.9 14 ꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏꠏ Data are number of patients. Numeric rating scale (NRS) ratio: initial NRS/final NRS, Dose ratio: initial dose/final dose (tablet), SE: side effects. A: cancer pain, B: musculoskeletal pain, C: neuropathy, D: osteoarthritis or rheumatic arthritis, M: others.
Fig. 1. Comparison of numeric rating scale (NRS) before and after tramadol/acetaminophen combination tablet treatment. Data are mean ± S.D. A: cancer pain, B: musculoskeletal pain, C: neuropathy, D: osteoarthritis or rheumatic arthritis, M: Others. *P ＜ 0.01: initial NRS vs. final NRS.
236
대한통증학회지：제 17 권 제 2 호 2004
medicated concurrently with other analgesics. The study period
In the evaluation of the efficacy of the tramadol/ acetamin-
of the tramadol/acetaminophen combination tablet effect was 4
ophen combination tablet for all patients, no relief (n=17),
weeks in 75 patients, 8 weeks in 99 patients, 12 weeks in 55
moderate relief (n=108), notable relief (n=95), significant relief
patients and more than 4 weeks in 17 patients (Table 1).
(n=23), and 3 were not assessed (Fig. 2). According to the
In all patients, the mean NRS score decreased from 6.1 to
categories no relief, moderate relief, notable relief, significant
3.5. In the cancer pain group, the mean NRS score decreased
relief, and not assessed, the number of patients in cancer pain
from 5.2 to 2.3, in the musculoskeletal group from 6.4 to
group were 2, 15, 24, 5 and 0; the musculoskeletal group
3.77, in the neuropathy group from 7.2 to 4.6, in the OA/RA
were 4, 23, 32, 4 and 1; the neuopathy group were 3, 10, 14,
group from 6.0 to 3.8 and in the other pain group from 6.2to
2 and 0; the OA/RA group were 7, 50, 22, 6 and 2, and the
1.2 (Fig. 1).
other pain group were 1, 10, 3, 6 and 0 (Fig. 3). The doctor's evaluation depended on the NRS score change, the pain relief score, the development of side effects, the patient's response, and the patient's age divided by not useful
Fig. 2. Efficacy of tramadol/acetaminophen combination tablet for all patients. Percent values are representing the number of patients of the corresponding categoried to the total patients. No relief: numeric rating scale (NRS) aggravation or no change, Moderate relief: NRS decrease 1-2, Notable relief: NRS decrease 3-4, Significant relief: NRS decrease 5 or more.
Fig. 3. Comparison of Pain relief after tramadol/acetaminophen combination tablet treatment. A: cancer pain, B: musculoskeletal pain, C: neuropathy, D: osteoarthritis or rheumatic arthritis.
Fig. 4. Doctors assessment for the usefulness of tramadol/ acetaminophen combination tablet in the management of chronic pain.
Fig. 5. Comparison of pain relief after tramadol/acetaminophen combination tablet treatment. A: cancer pain, B: musculoskeletal pain, C: neuropathy, D: osteoarthritis or rheumatic arthritis.
237
SH Baek, et al：Tramadol/Acetaminophen Combination Tablets for Chronic Pain Treatment
(n=29), useful (n=188), and very useful (n=20). Nine (9) pa-
Also, tramadol is an effective and safe drug for long term use
tients are not assessed (Fig. 4, 5).
in arthritis pain.
Side effects developed in only 14 patients during this study,
A recent study has demonstrated the effect of tramadol/
but adverse effects were not severe and were soon remedied.
acetaminophen combination tablet in the treatment of acute or
These were nausea, somnolence, dizziness and constipation (Ta-
chronic pain.
ble 1).
combination tablet, so they had a wash out period more than
1,15)
They evaluated only tramadol/acetaminophen
3 weeks, but in our study we used other drug in combination. During this study, coexisting drug dosage did not change, but
DISCUSSION
maintained throughout the study period. Therefore, we conThe purpose of combination analgesics is to improve the ef-
cluded that tramadol/acetaminophen combination tablet is an ef-
fect of simple analgesics and to reduce side effects or toxic-
fective adjuvant analgesic chronic pa.in management. Most of
6)
Tramadol/acetaminophen combination tablet is a combina-
all case used other analgesics before tramadol/acetaminophen
tion analgesic having different action mechanisms, so it has a
combination tablet had taken, but pain was not controlled. Af-
synergic effect. Its benefits are the complementary actions of
ter 4 weeks or a longer period during which Ultracet
the constituent analgesics: the rapid effect of acetaminophen
administered, significantly decreased NRS scores and pain re-
and the sustained effect of tramadol.7,8) Tramadol/acetaminophe
lief. Before our study began, many patients had experienced
combination tablet is not a nonsteroidal anti-inflammatory drug
adverse effects due to the high dosage of other analgesics, but
(NSAID); it is not associated with gastrointestinal bleeding and
after our study, most patients did not experience adverse ef-
ulcers. In clinical trials, constipation, somnolence, and increased
fects. Tramadol/acetaminophen combination tablet, a low dosage
sweating were the most frequent adverse effects associated with
of each medication can be administered, side effects are mini-
ity.
Ⓡ
Ultracet ; these were not significant and were soon remedied. The efficacy of the Tramadol/acetaminophen combination
Ⓡ
was
mized, and a better result is achieved by this synergic mechanism.
tablet in all patients' groups was a significant decrease in NRS
We concluded that tramadol/acetaminophen combination tab-
from 6.1 to 3.5. We analyzed followed by four groups (P ＜
let is an effective analgesic in acute or chronic pain manage-
0.01). In the cancer group, the NRS decreased from 5.2 to 2.3
ment, which makes it a first-line or adjuvant analgesic.
and 63% of patients' pain relief evaluations were notable or significant pain relief. The WHO has recognized combination
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A recent study
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13)
In the OA/RA pain group, the NRS
decreased from 6.1 to 3.8, and 32% of patients' pain relief evaluations were notable or significant pain relief. Acetaminophen is a first-line therapy in OA/RA patients because of its rapid action time, safety, and lower incidence of side effects.
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